Process for 5-fluoro-6-chlorooxindole

ABSTRACT

Process for the production of 5-fluoro-6-chloro- oxindole, (III), which is useful in the synthesis of certain analgesic and antiinflammatory agents, via two different synthetic pathways. 
     Compounds of formula (I) and (II) shown below ##STR1## which are intermediates in the process of this invention.

This ia a division of application Ser. No. 07/720,974, filed on Jun. 25,1991, now U.S. Pat. No. 5,166,401.

BACKGROUND OF THE INVENTION

The present invention is directed to processes for the preparation of5-fluoro-6-chlorooxindole (III). 5-Fluoro-6-chlorooxindole isparticularly useful as an intermediate in the synthesis of certainanalgesic and antiinflammatory agents having the formula ##STR2##wherein R¹ is selected from the group consisting of alkyl having 1 to 6carbons, cycloalkyl having 3 to 7 carbons, cycloalkenyl having 4 to 7carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbonsin said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in saidalkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substitutedphenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkylhaving 1 to 3 carbons in said alkyl, naphthyl,bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]-hept-5-en-2-yl and -(CH₂)_(n)-Q-R; wherein the substituent on said substituted phenyl, said(substituted phenyl)alkyl and said (substituted phenoxy)alkyl isselected from the group consisting of fluoro, chloro, bromo, alkylhaving 1 to 4 carbons, alkoxy having 1 to 4 carbons and trifluoromethyl;n is zero, 1 or 2; Q is a divalent radical derived from a compoundselected from the group consisting of furan, thiophene, pyrrole,pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole,1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole,tetrahydrofuran, tetrahydro-thiophene, tetrahydropyran,tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo[b] furan andbenzo[b] thiophene; and R is hydrogen or alkyl having 1 to 3 carbons.

The compounds of the formula (A), their preparation and their utility asan analgesic and antiinflammatory agents are fully described herein andin U.S. Pat. No. 4,556,672.

5-Fluoro-6-chlorooxindole has been previously prepared by Kadin, U.S.Pat. No. 4,556,672, via 3-chloro-4-fluoro-aniline which was reacted withchloroacetyl chloride to produceN-(2-chloroacetyl)-3-chloro-4-fluoroaniline, which in turn was cyclizedin the presence of a strong alkali metal halide (Lewis Acid, e.g.,aluminum chloride) to produce 5-fluoro-6-chlorooxindole.

Similar types of reactions, as illustrated in Scheme 2, using hydrogenfluoride-pyridine to rearrange an aromatic hydroxylamine iswell-documented in the literature: Fidler et al., J. Org. Chem., 26,4014 (1961), Patrick al. J. Org. Chem., 39. 1758 (1974). Incorporating anitrile in the reaction to obtain the desired compound (III) from (IV)is novel and not anticipated by the literature. The desired compound(III) is not obtained, in the absence of an alkyl or aryl nitrile, when(IV) is reacted with hydrogen fluoride-pyridine or anhydrous hydrogenfluoride alone.

This invention also relates to the novel compounds (I) and (II) havingthe formulas ##STR3## which are intermediates formed in the process ofthis invention and which therefore are useful for the production of thecompound with formula (III).

SUMMARY OF THE INVENTION

We have now found that 5-fluoro-6-chlorooxindole (III) can besynthesized by either of two new processes, Method A or Method B, whichaffords a much higher yield of compound III) than the process cited inU.S. Pat. No. 4,556,672.

Method A comprises the steps of:

(a) rearranging methyl 2-(2-hydroxylamine-4-chloro-phenyl)acetate (I)with a hydrogen fluoride source (e.g., anhydrous hydrogen fluoride orhydrogen fluoride-pyridine) to produce methyl(2-amino-4-chloro-5-fluorophenyl)acetate (II); and

(b) cyclizing (II) with an acid in either an aqueous or organiccosolvent to produce the compound, 5-fluoro-6-chlorooxindole (III).

Method B comprises rearranging 5-chloro-1-hydroxy-oxindole (IV) with ahydrogen fluoride source (e.g., hydrogen fluoride-pyridine), in thepresence of an alkyl or aryl nitrile to produce5-fluoro-6-chloro-oxindole (III).

Method A is shown in Scheme i and Method B in Scheme 2. ##STR4##

The present invention is also directed to compound of the formula##STR5## which are particularly vaulable intermediates in thepreparation of the compounds of the formula (III).

DETAILED DESCRIPTION OF THE INVENTION

The overall processes of this invention are shown in Scheme 1 and Scheme2.

The starting compound (I) in Scheme 1 is readily prepared from methyl2-(2-nitro-4-chlorophenyl)acetate, 5% palladium on carbon, sodiumhypophosphite and water, pursuant to the reactions described byJohnstone, et al., Tetrahedron 34, 213, (1978). In step [a] compound (I)is reacted with either hydrogen fluoride-pyridine or anhydrous hydrogenfluoride. In the case of hydrogen fluoride-pyridine, compound (I) isdissolved in a minimum amount of pyridine and added to an ice-bathcooled solution of the hydrogen fluoride-pyridine. After the addition,the temperature of the reaction is raised to 25° C. to 50° C. and thetwo reagents are allowed to react for one hour. The reaction mixture iscooled to room temperature and the pH of the mixture adjusted to 7 usinga solution of weak base, preferably sodium carbonate. In the case ofanhydrous hydrogen fluoride, compound (I) is cooled to -78° C. in areaction vessel, anhydrous hydrogen fluoride is condensed into thereaction vessel and the vessel is sealed. The reaction mixture is warmedto 25° C. to 50° C. and stirred for between 3 to 4 hours. The reactionvessel is opened and excess hydrogen fluoride is aspirated off. Ineither case rearrangement occurs to produce methyl(2-amino-4-chloro-5-fluorophenyl)acetate (II). Compound (II) can bepurified by standard techniques well known to those skilled in the art.Alternatively, compound (II) can be used directly for the next reactionstep.

Compound (III) is obtained by cyclizing (II) with an acid as shown instep [b] of Scheme 1. Compound (II) is dissolved in a mixture of an acidand a cosolvent, preferably the acid is glacial acetic acid in whichinstance the preferred cosolvent is water or the acid is hydrochloricacid in which instance the preferred cosolvent is methylene chloride.With acetic acid the ratio of the acid and cosolvent mixture ranges from2:1 to pure acetic acid respectively, the preferred ratio being 6:1.With HCl, much less acid is required, preferably 1:4 3N HCl to CH₂ Cl₂.Once compound (II) is dissolved, the reaction mixture is stirred atambient temperature for from 6 to 7 hours to produce5-fluoro-6-chlorooxindole (III). Compound (III) is readily purified byrecrystallization from ethyl acetate to yield an off-white solid.

Alternatively, compound (III) can be obtained by the reaction shown inScheme 2. The starting compound (IV) is readily prepared by the reactionof compound (I) with a catalytic amount of 50% sulfuric acid. After 18hours, the reaction mixture is filtered and compound (IV) is obtained asa yellow solid.

Compound (III) can be obtained by reaction of compound (IV) withhydrogen fluoride-pyridine in the presence of an alkyl or aryl nitrile.Compound (IV) and hydrogen fluoride-pyridine are mixed with an alkyl oraryl nitrile, preferably methoxyacetonitrile, acetonitrile or2-cyanopyridine, in a reaction vessel. The vessel is sealed and thereaction mixture temperature is raised to 25° C. to 50° C. and stirredfor approximately between 12 to 24 hours, 18 hours is preferred. Afterisolation by conventional means well known to those skilled in the art,a tan solid is obtained.

The following examples serve to illustrate the invention and are not tobe construed as limiting the scope of this invention to the embodimentsso exemplified. Nuclear magnetic resonance spectra (NMR) were measuredon a 300 MHz instrument and peak positions are expressed in parts permillion (ppm). The peak shapes are denoted as follows: s, singlet; br,broad; d, doublet; t, triplet; q, quartet; m, multiplet. "J" denotes thesplitting constant which is also expressed in ppm.

EXAMPLE 1 Methyl (4-chloro-2-N-hydroxyamino] phenyl)acetate (I)

Methyl (2-nitro-4-chlorophenyl)acetate (5.0 g, 21.7 mmol) was dissolvedin 250 ml of tetrahydrofuran and 15 ml of dimethyl sulfoxide. To thiswas added 900 mg of 10% pd/C. A solution of 5.38 g of sodiumhypophosphite in 18 ml of water was added dropwise over a 40 minuteperiod. After stirring for 4 hours another 2.68 g of sodiumhypophosphite (in 8 ml of water) was added over a 10 minute period.After stirring for one hour the reaction mixture was filtered throughCelite and the filtrate diluted with 500 ml of CH₂ Cl₂. The filtrate waswashed with saturated aqueous NaHCO₃ then brine and dried with Na₂ SO₄.The solvents were evaporated under reduced pressure leaving 5.16 g of ayellow oil (110% of theory). NMR (300 MHz, CDCl₃) 3.51 (2H, s), 3.69(3H, s), 5.50 (1H, br s), 6.88 (1H, dd, J=1,8), 7.01 (1H, d, J=8), 7.34(1H, d, J=1), 7.56 (1H, br s).

EXAMPLE 2 Methyl (2-amino-4-chloro-5-fluorophenyl)acetate (II), Hydrogenfluoride-pyridine method

A polypropylene flask containing 57 ml of HF-pyridine was cooled in anice bath. Hydroxylamine (I) (2.34 g, 10.9 mmol) was added portionwiseover a 12 minute period as a solution in 2 ml of pyridine. After theaddition was complete the ice bath was removed and the mixture waswarmed to 35° C. for 1 hour. After cooling to room temperature thereaction mixture was cautiously added to a solution of 115 g of Na₂ CO₃in 290 ml of water. The pH of the solution was , adjusted to 7 byaddition of more Na₂ CO₃ then extracted with ethyl acetate (3×300 ml).The combined ethyl acetate extracts were washed with water (2×200 ml)then brine (200 ml) and dried with MgSO₄. Removal of the solventsyielded 2.18 g of a tan solid. NMR (300 MHz, DMSO-d₆) 3.57 (2H, s), 3.63(3H, s), 5.11 (2H, br s), 6.79 (1H, d, J=8), 7.06 (1H, d, J=10).

EXAMPLE 3 Methyl (2-amino-4-chloro-5-fluorophenyl)acetate (II), Anydroushydrogen fluoride method

Hydroxylamine (I) (0.50 g, 2.32 mmol) and a magnetic stir bar were addedto a 100 ml teflon vessel. Cooled to -78° C. and 25 ml of anhydrous HFwas condensed into the vessel. The vessel was sealed and allowed to warmto 20° C. The mixture was stirred for 3.4 hours at which time the vesselwas opened and the HF removed under aspirator vacuum. The residue wasdissolved in 50 ml of CH₂ Cl₂ and washed with saturated aq. NaHCO₃ anddried with Na₃ SC₄. Filtration and removal of solvents under vacuumyielded 0.41 g of a brown oil. The NMR was identical to that prepared bythe HF-pyridine method.

EXAMPLE 4 5-Fluoro-6-chlorooxindole (III) From (II)

A crude amount of (II) (2.18 g) was dissolved in 60 ml of 6:1 HOAc/H₂ Oand stirred for 6.5 hours. The solvents were evaporated under vacuumgiving 1.93 g of a tan solid. The crude oxindole was recrystallized fromethyl acetate producing 1.2 g of an off-white solid. NMR (300 MHz,DMSO-d₆), 3.50 (2H, s), 6.89 (1H, d, J=7), 7.32 (1H, d, J=8), 10.50 (1H,br, s).

EXAMPLE 5 5-Fluoro-6-chlorooxindole (III) From (IV)

In a polypropylene flask was placed 20 ml of HF-pyridine. Then 4 ml of2-cyanopyridine was added followed by 2.0 g (10.9 mmol) of (IV). Theflask was sealed and heated to 45° C. for 18 hours. The reaction mixturewas poured into 160 ml of water and extracted with ethyl acetate (3×200ml). The combined ethyl acetate extracts were washed with 5% HCl (3×100ml) and dried with MgSC₄. Filtration and evaporation of the solventsleft 3.39 9 of a waxy brown solid that still contained 2-cyanopyridine.Trituration of this solid with isopropyl ether removed the2-cyanopyridine leaving 1,80 g of a tan solid. The NMR of this materialwas identical to that obtained in Example 4.

PREPARATION 1 5-Chloro-1-hydroxyoxindole (IV)

The hydroxylamine (I) (200 mg, 0.92 mmol) was dissolved in 10 ml ofethanol. Then 8 drops of 50% H₂ SO₄ was added. After 10 minutes a creamcolored solid began to precipitate. The mixture was stirred at roomtemperature for 18 hours. The reaction was diluted with ethyl acetate(100 ml) washed with sat. aq. NaHCO₃ and dried with Na₂ SC₄. Afterfiltration, the solvents were evaporated under reduced pressure yielding111 mg of a yellow solid. mp 202-208° C. NMR (300 MHz, DMSO-d₆) 3.58(2H, s), 6.95 (1H, d, J=1) , 7.06 (1H, dd, J=1,8), 7.26 (1H, d, J=8),10.9 (1H, br, s).

I claim:
 1. A process for the preparation of a compound of the formula##STR6## which comprises of rearranging a compound of the formula##STR7## with a hydrogen fluoride source in the presence of an alkyl oraryl nitrile to produce compound (III).
 2. The process of claim 1wherein the hydrogen fluoride source is hydrogen fluoride-pyridine. 3.The process of claim 1 which uses an alkyl nitrile and said alkylnitrile is methoxyacetonitrile or acetonitrile.
 4. The process of claim1 which uses an aryl nitrile and said aryl nitrile is 2-cyanopyridine.5. The process of claim 1 wherein the temperature of the reaction iscontrolled to from about 25.20 C. to 50° C.